Hyperhomocycteinemia (HHcy) is an independent risk factor for cardiovascular disease in the general population and associated with vascular diseases in diabetic patients{Hackam, 2003 #101;Schnyder, 2002 #102;Schnyder, 2002 #102}. When diabetes is compounded HHcy, cardiovascular mortality is about 2-fold greater than in those without HHcy. We have obtained substantial preliminary data showing that the combination of HHcy and Hyperglycemia (HHcy/HG) accelerated the development of atherosclerotic lesion, increased monocyte (MC)/macrophage (M) in the lesion, elevated inflammatory subsets of MC and M (Ly6Cmiddle+high MC and M1 M) in peripheral tissues. It is known that inflammatory MC and M contribute to vascular and systemic inflammation. In this proposal, we will examine the role and mechanism of Hcy in MC/M differentiation and in vascular inflammation, a key status determining atherosclerosis and cardiovascular disease, in combinatory diseases of HHcy and diabetes. Our central hypothesis is that HHcy promotes inflammatory MC/M differentiation via DNA hypomethylation thereby accelerating atherogenesis in diabetes. We will test our hypothesis by using the following three Aims: Aim 1 will examine the effect of HHcy on inflammatory MC/M differentiation and vascular diseases in diabetes animals. Aim 2 will access mechanisms contributing to HHcy-induced MC differentiation in T2DM. Aim 3 will identify the role of DNA hypomethylation in mediating HHcy- induced MC differentiation and test a novel DNA methylation therapy in preventing inflammatory MC/M differentiation and vascular diseases in diabetes animals. Success of this project will lead to the development of novel therapeutics for HHcy- related diabetic cardiovascular disease.